The hVps34‐ SGK 3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC 1 and tumour growth

Abstract

We explore mechanisms that enable cancer cells to tolerate PI3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK3 that is related to Akt. Under these conditions, SGK3 is controlled by hVps34 that generates PtdIns(3)P, which binds to the PX domain of SGK3 promoting phosphorylation and activation by its upstream PDK1 activator. Furthermore, under conditions of prolonged PI3K/Akt pathway inhibition, SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1. We characterise 14h, a compound that inhibits both SGK3 activity and activation in vivo, and show that a combination of Akt and SGK inhibitors induced marked regression of BT‐474 breast cancer cell‐derived tumours in a xenograft model. Finally, we present the kinome‐wide analysis of mRNA expression dynamics induced by PI3K/Akt inhibition. Our findings highlight the importance of the hVps34‐SGK3 pathway and suggest it represents a mechanism to counteract inhibition of PI3K/Akt signalling. The data support the potential of targeting both Akt and SGK as a cancer therapeutic.

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

“…The almost undetectable expression of Sgk2 suggests that this isoform is unlikely to play a critical role in the control of thyroid cell proliferation. On the other hand, Sgk3 is unique among the SGK genes, since it has a N-terminal PX-domain targeting the protein to the endosomes, where it is activated in response to the class III PI3K Vps34 (23). Based on these notions, as well as on preliminary shRNA-based experiments showing very limited effects of Sgk3 depletion on cell proliferation (Suppl.…”

The PI3K Pathway in Human Disease

“…Analysis of 18 biopsies from patients treated with alpelisib showed that samples with high SGK1 mRNA and phospho-N-Myc downstream regulated 1 (NDRG1; a substrate for and biomarker of SGK1 activation) levels correlated with intrinsic resistance to alpelisib, whereas most phospho-NDRG1-negative tumors were from patients who attained partial responses or stable disease. Similarly, SGK3 overexpression and/or activation has been repeatedly linked to PI3K/mTOR inhibitor resistance in breast cancer cells (Bago et al, 2016; Gasser et al, 2014). These reports offer a common mechanism for intrinsic or acquired resistance to PI3K or AKT inhibitors.…”

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

“…SGK3 has been shown to play a pivotal role in Akt-independent signaling downstream of oncogenic PIK3CA mutations in some human cancers, including breast cancer (11). Most recently, Bago et al reported that SGK3 counteracts the inhibition of PI3K/Akt signaling and stimulates tumor growth (12). SGK3 is amplified and hyperactivated in breast cancer (13), and its expression is regulated by ERα and positively correlates with ERα levels in breast tumors (14,15).…”